US4879304A - Ophthalmic compositions and process for preparing - Google Patents

Ophthalmic compositions and process for preparing Download PDF

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Publication number
US4879304A
US4879304A US07/045,913 US4591387A US4879304A US 4879304 A US4879304 A US 4879304A US 4591387 A US4591387 A US 4591387A US 4879304 A US4879304 A US 4879304A
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composition
viscosity
ophthalmic
centistokes
polydimethylsiloxane
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US07/045,913
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Ronald D. Schoenwald
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Angelini Pharma Inc
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Angelini Pharma Inc
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Priority to US07/045,913 priority Critical patent/US4879304A/en
Priority to EP88101032A priority patent/EP0288659A1/en
Assigned to ANGELINI PHARMACEUTICALS LTD. reassignment ANGELINI PHARMACEUTICALS LTD. ASSIGNMENT OF ASSIGNORS INTEREST. Assignors: SCHOENWALD, RONALD D.
Priority to JP10738588A priority patent/JPS6452722A/en
Priority to CA000565504A priority patent/CA1309348C/en
Priority to AU15315/88A priority patent/AU609803B2/en
Priority to KR1019880008502A priority patent/KR890011602A/en
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Publication of US4879304A publication Critical patent/US4879304A/en
Anticipated expiration legal-status Critical
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/695—Silicon compounds
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/0012—Galenical forms characterised by the site of application
    • A61K9/0048—Eye, e.g. artificial tears
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
    • A61K47/24—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing atoms other than carbon, hydrogen, oxygen, halogen, nitrogen or sulfur, e.g. cyclomethicone or phospholipids
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/30—Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
    • A61K47/34—Macromolecular compounds obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyesters, polyamino acids, polysiloxanes, polyphosphazines, copolymers of polyalkylene glycol or poloxamers

Definitions

  • a pharmaceutical vehicle In order for a pharmaceutical vehicle to be useful as an ophthalmic vehicle, it is necessary that it be non-irritating to the eye, and non-toxic. In order for it to be most effective it must not blur the vision. For certain drugs, unstable in aqueous solution an oil based vehicle is required. For other drugs, which are water soluble and poorly absorbed, it is possible to promote better bioavailablility through the use of an oil vehicle (Biopharm. and Drug Disposite, Vol. 7 page 453, 1986). Nevertheless, known oil based ophthalmic vehicles blur the eye.
  • Known vehicles are edible vegetable oils such as cottonseed oil, soybean oil, coconut oil, rapeseed oil, peanut oil, olive oil, palm oil, palm kernel oil, castor oil, sunflower seed oil, wall flower oil, sesame oil; or mineral oils. None of these previously known oils satisfy the 3 above mentioned criteria; all of these oils, while being nonirritating and toxic, blur the vision.
  • the present invention provides ophthalmic drugs, in an oil based vehicle which is non-irritating, non-toxic and yet does not blur the vision.
  • polydimethylsiloxane at a viscosity of 3-70 centistokes is useful as a unique ophthalmic vehicle which does not blur vision, is non-toxic and non-irritating to the eye.
  • Polydimethylsiloxane, at a viscosity of 3-70 centistokes may be combined with various opthalmic drugs to provide novel ophthalmic compositions.
  • Polydimethylsiloxane of the above mentioned viscosity may for example be combined with oxazolidine pro-drugs of 3-hydroxy-x - [methylamino T methyl] benzyl alcohol commonly known as phenylephrine, of the formula II ##STR1## wherein R 1 , R 2 , and R 3 are any aliphatic combinations of C 1 -C 5 , and R 1 may also be hydrogen or the non-toxic pharmaceutically acceptable salt forms thereof; to provide a stable, ophthalmic composition.
  • Phenylephrine is a well-known pharmaceutically active amine whose principal use in the field of ophthalmology is as a mydriatic.
  • phenylephrine is a well-known pharmaceutically active amine whose principal use in the field of ophthalmology is as a mydriatic.
  • Those disadvantages have limited the use of this highly effective drug.
  • it is one of the most effective mydriatics available, its use is significantly limited because of the significant side effects which may occur in some individuals treated with phenylephrine. Those unwanted significant side effects range from hypertension, syncope, and even in some cases to myocardial infarction, leading to death. Such side effects have been reported with doses of topical ocular phenylephrine.
  • prodrug refers to a therapeutic agent that requires enzymatic transformation to demonstrate therapeutic activity.
  • the prodrug itself is not therapeutically active, but once subjected to enzymatic activity by the host organism it is converted to an active drug.
  • some attempts to make prodrugs of phenylephrine with varying degrees of success. For example, Mindel et al, "Is Phenylephrine Pivalate a Prodrug?", Arch. Ophthalmol..
  • ephedrine is not commonly used ophthalmically and is biologically different in activity than phenylephrine, with ephedrine being used orally for nacolepsy, bronchial asthma and nasal congestion.
  • the oxazolidine derivative of phenylephrine increases the bulk considerably on the amine function, the latter of which is responsible for phenylephrine's activity.
  • the prodrug would be expected to be devoid of alphaadrenergic activity (A. Burger, "Medicinal Chemistry, 3rd ed., Wiley-Interscience, 1970, p. 1248).
  • the prodrug of phenylephrine is not stable in aqueous solution. Thus, it is necessary that effective ophthalmic compositions include the prodrug in an oil suspension.
  • composition of the invention is the only manner in which the prodrug can be delivered to the eye in a non-irritating, non-toxic manner without blurring the vision.
  • Polydimethylsiloxane of a viscosity of 30-70 centistokes may also for example, be combined with the mydriatic drug dapiprazole of the formula III ##STR2## to provide a non-irritating, non-toxic, non-blurring ophthalmic composition.
  • the compounds of formula II or III themselves, or their base form or pharmaceutically acceptable nontoxic acid salts thereof can be combined with the polydimethylsiloxane with a viscosity of 3-70 centistokes.
  • Such acid salt forms of biologically active compounds which are non-toxic are for example, those derived from inorganic acids such as hydrochloric, hydrobromic, sulfuric, sulfamic, phosphoric, nitric, and the like; and the salts prepared from organic acids such as acetic, propionic, succinic, glycollic, stearic, lactic, malic, tartaric, citric, ascorbic, pamoic, maleic, benzoic, glutamic and salicyclic.
  • Such pharmaceutically accepted salts of the base form of the compounds of formula II or III in the previously synthesized by conventional, chemical methods are prepared by reacting the free base form with stoichiometric amounts or with an excess thereof of the desired salt forming inorganic or organic acid, in a suitable solvent, or various combinations of solvents.
  • the free base can be dissolved in a mixed aqueous solution of the appropriate acid and the salt recovered by standard techniques, such as evaporation of the solution.
  • the amount of prodrug in the ophthalmic composition of the present invention can comprise from about 0. 00125% by weight of the composition up to about 10% by weight of the composition which is to be topically applied to the eye.
  • the composition is from about 0.5% by weight of the prodrug of phenylephrine (formula II) or dapiprazole (formula III) up to about 5% by weight of the prodrug or dapiprazole.
  • the balance of the composition is primarily the silicone fluid (polydimethylsiloxane) at a viscosity of 3-70 centistokes.
  • the pharmaceutical composition may contain other non-toxic auxiliary substances such as anti-bacterials, anti-fungals, anti-oxidants, wetting agents, preservatives and the like.
  • auxiliary substances such as anti-bacterials, anti-fungals, anti-oxidants, wetting agents, preservatives and the like.
  • antibacterial components such as chlorobutanol, methyl and propyl paraben, and to the degree they are soluble quaternary ammonium compounds, phenylmercuric salts known to have cold sterilizing properties and which are non-injurious in use, and thimerosal
  • wetting agents such as pluronic P-103, SPAN with low HLB values (HLB below 5)
  • antifungals such as methyl and propyl paraben
  • preservatives such as alpha-topocerol and BHA
  • other conventional ingredients such as sorbitan monolaurate, triethanolamine oleate, polyoxyethylene sorbitan monopalmitylate, dioctyl sodium
  • DOW CORNING 360 MEDICAL FLUID A source of polydimethysiloxane of a viscosity of 3-70 centistokes is DOW CORNING 360 MEDICAL FLUID.
  • DOW CORNING 360 MEDICAL FLUID can be purchased at a viscosity of 3, 20, 100 centistokes, and to make polydimethylsiloxane of intermediate viscosity one simply appropriately dilutes one viscosity of the DOW CORNING 360 MEDICAL FLUID with another. For example, to obtain a viscosity of 11.5, DOW 360 with a viscosity of 3 and 20 centistokes is mixed 1:1.
  • the invention also relates to preparing the ophthalmic composition.
  • the ophthalmic drug of choice is micronized to prevent corneal abrasion.
  • a wetting agent is added to permit interaction between the polydimethylsiloxane and the drug.
  • About 25% of the desired amount of polydimethylsiloxane is mixed with the drug and wetting agent, and the solution is mixed, preferably in a high speed mixer The remainder of the polydimethylsiloxane is then added.
  • other auxiliary substances may be then added as desired.
  • An example of typical pharmaceutical composition to be used with the compound 2-t-butyl-3-methyl-5-(m-hydroxyphenly)-1,3-oxazolidine in its base form includes the following:

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  • Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Veterinary Medicine (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Epidemiology (AREA)
  • Medicinal Chemistry (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Molecular Biology (AREA)
  • Biophysics (AREA)
  • Ophthalmology & Optometry (AREA)
  • Engineering & Computer Science (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • General Chemical & Material Sciences (AREA)
  • Oil, Petroleum & Natural Gas (AREA)
  • Proteomics, Peptides & Aminoacids (AREA)
  • Inorganic Chemistry (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Medicinal Preparation (AREA)

Abstract

The present invention relates to novel therapeutic opthalmic compositions containing polydimethylsiloxane, and a process for preparing such ophthalmic compositions.

Description

SUMMARY OF THE INVENTION
In order for a pharmaceutical vehicle to be useful as an ophthalmic vehicle, it is necessary that it be non-irritating to the eye, and non-toxic. In order for it to be most effective it must not blur the vision. For certain drugs, unstable in aqueous solution an oil based vehicle is required. For other drugs, which are water soluble and poorly absorbed, it is possible to promote better bioavailablility through the use of an oil vehicle (Biopharm. and Drug Disposite, Vol. 7 page 453, 1986). Nevertheless, known oil based ophthalmic vehicles blur the eye. Known vehicles are edible vegetable oils such as cottonseed oil, soybean oil, coconut oil, rapeseed oil, peanut oil, olive oil, palm oil, palm kernel oil, castor oil, sunflower seed oil, wall flower oil, sesame oil; or mineral oils. None of these previously known oils satisfy the 3 above mentioned criteria; all of these oils, while being nonirritating and toxic, blur the vision.
The present invention provides ophthalmic drugs, in an oil based vehicle which is non-irritating, non-toxic and yet does not blur the vision.
DETAILED DESCRIPTION OF THE INVENTION
It is a discovery of the invention that polydimethylsiloxane at a viscosity of 3-70 centistokes, is useful as a unique ophthalmic vehicle which does not blur vision, is non-toxic and non-irritating to the eye.
Polydimethylsiloxane, at a viscosity of 3-70 centistokes may be combined with various opthalmic drugs to provide novel ophthalmic compositions.
Polydimethylsiloxane of the above mentioned viscosity, may for example be combined with oxazolidine pro-drugs of 3-hydroxy-x - [methylamino T methyl] benzyl alcohol commonly known as phenylephrine, of the formula II ##STR1## wherein R1, R2, and R3 are any aliphatic combinations of C1 -C5, and R1 may also be hydrogen or the non-toxic pharmaceutically acceptable salt forms thereof; to provide a stable, ophthalmic composition.
Phenylephrine is a well-known pharmaceutically active amine whose principal use in the field of ophthalmology is as a mydriatic. There are, however, certain known disadvantages associated with the use of phenylephrine as a mydriatic agent. Those disadvantages have limited the use of this highly effective drug. Thus, in spite of the fact that it is one of the most effective mydriatics available, its use is significantly limited because of the significant side effects which may occur in some individuals treated with phenylephrine. Those unwanted significant side effects range from hypertension, syncope, and even in some cases to myocardial infarction, leading to death. Such side effects have been reported with doses of topical ocular phenylephrine.
One approach which has been used from time to time in the past is the effort to develop successful prodrugs of phenylephrine. The term prodrug refers to a therapeutic agent that requires enzymatic transformation to demonstrate therapeutic activity. In other words, the prodrug itself is not therapeutically active, but once subjected to enzymatic activity by the host organism it is converted to an active drug. In the past there have been some attempts to make prodrugs of phenylephrine, with varying degrees of success. For example, Mindel et al, "Is Phenylephrine Pivalate a Prodrug?", Arch. Ophthalmol.. 98, 2220 (1980) suggests the reaction product of phenylephrine and pivalic acid to provide a pivalic acid ester as a possible prodrug. However, as reported in that article, phenylephrine pivalate itself produces these side effects. And, it goes without saying that to have a successful prodrug, the prodrug itself must not produce the unwanted side effects, even though it may be effectively converted within the body to the active drug. Johansen et al, "Prodrugs as Drug Delivery Systems XXV: Hydrolysis of Oxazolidines--A Potential New Prodrug Type", Journal Pharm. Sci., 72, 1294 (1983) discloses some prodrug possibilities of ephedrine. However, ephedrine is not commonly used ophthalmically and is biologically different in activity than phenylephrine, with ephedrine being used orally for nacolepsy, bronchial asthma and nasal congestion. In contrast, the oxazolidine derivative of phenylephrine increases the bulk considerably on the amine function, the latter of which is responsible for phenylephrine's activity. With the addition of oxazolidine to the amine function, the prodrug would be expected to be devoid of alphaadrenergic activity (A. Burger, "Medicinal Chemistry, 3rd ed., Wiley-Interscience, 1970, p. 1248).
Accordingly, there is a continuing and real need for safe and effective prodrugs of phenylephrine which can be safely and effectively delivered to the eye.
The prodrug of phenylephrine is not stable in aqueous solution. Thus, it is necessary that effective ophthalmic compositions include the prodrug in an oil suspension.
The composition of the invention is the only manner in which the prodrug can be delivered to the eye in a non-irritating, non-toxic manner without blurring the vision.
Polydimethylsiloxane of a viscosity of 30-70 centistokes may also for example, be combined with the mydriatic drug dapiprazole of the formula III ##STR2## to provide a non-irritating, non-toxic, non-blurring ophthalmic composition.
The compounds of formula II or III themselves, or their base form or pharmaceutically acceptable nontoxic acid salts thereof can be combined with the polydimethylsiloxane with a viscosity of 3-70 centistokes. Such acid salt forms of biologically active compounds which are non-toxic are for example, those derived from inorganic acids such as hydrochloric, hydrobromic, sulfuric, sulfamic, phosphoric, nitric, and the like; and the salts prepared from organic acids such as acetic, propionic, succinic, glycollic, stearic, lactic, malic, tartaric, citric, ascorbic, pamoic, maleic, benzoic, glutamic and salicyclic.
Such pharmaceutically accepted salts of the base form of the compounds of formula II or III in the previously synthesized by conventional, chemical methods. Generally the salts are prepared by reacting the free base form with stoichiometric amounts or with an excess thereof of the desired salt forming inorganic or organic acid, in a suitable solvent, or various combinations of solvents. For example the free base can be dissolved in a mixed aqueous solution of the appropriate acid and the salt recovered by standard techniques, such as evaporation of the solution.
The amount of prodrug in the ophthalmic composition of the present invention can comprise from about 0. 00125% by weight of the composition up to about 10% by weight of the composition which is to be topically applied to the eye. Preferably the composition is from about 0.5% by weight of the prodrug of phenylephrine (formula II) or dapiprazole (formula III) up to about 5% by weight of the prodrug or dapiprazole. The balance of the composition is primarily the silicone fluid (polydimethylsiloxane) at a viscosity of 3-70 centistokes.
The pharmaceutical composition, besides the silicone fluid (polydimethylsiloxane) may contain other non-toxic auxiliary substances such as anti-bacterials, anti-fungals, anti-oxidants, wetting agents, preservatives and the like. Examples include antibacterial components such as chlorobutanol, methyl and propyl paraben, and to the degree they are soluble quaternary ammonium compounds, phenylmercuric salts known to have cold sterilizing properties and which are non-injurious in use, and thimerosal; wetting agents such as pluronic P-103, SPAN with low HLB values (HLB below 5); antifungals such as methyl and propyl paraben; preservatives such as alpha-topocerol and BHA; and other conventional ingredients such as sorbitan monolaurate, triethanolamine oleate, polyoxyethylene sorbitan monopalmitylate, dioctyl sodium sulfosuccinate, monothioglycerol, thiosorbitol, and ethylenediamine tetracetic acid, to the degree they are soluble, and the like.
A source of polydimethysiloxane of a viscosity of 3-70 centistokes is DOW CORNING 360 MEDICAL FLUID. DOW CORNING 360 MEDICAL FLUID can be purchased at a viscosity of 3, 20, 100 centistokes, and to make polydimethylsiloxane of intermediate viscosity one simply appropriately dilutes one viscosity of the DOW CORNING 360 MEDICAL FLUID with another. For example, to obtain a viscosity of 11.5, DOW 360 with a viscosity of 3 and 20 centistokes is mixed 1:1.
The invention also relates to preparing the ophthalmic composition.
Generally, the ophthalmic drug of choice is micronized to prevent corneal abrasion. A wetting agent is added to permit interaction between the polydimethylsiloxane and the drug. About 25% of the desired amount of polydimethylsiloxane is mixed with the drug and wetting agent, and the solution is mixed, preferably in a high speed mixer The remainder of the polydimethylsiloxane is then added. As indicated above, other auxiliary substances may be then added as desired.
An example of typical pharmaceutical composition to be used with the compound 2-t-butyl-3-methyl-5-(m-hydroxyphenly)-1,3-oxazolidine in its base form, includes the following:
______________________________________                                    
Ingredients            Percent                                            
______________________________________                                    
2-t-butyl-3-methyl-5-(m-hydroxy-                                          
                       1.00                                               
phenyl)-1,3-oxazolidine                                                   
Chlorobutanol          0.25                                               
Wetting Agent, Arlacel-85                                                 
                       0.05                                               
Dow 360 Medical Fluid, 3 centistokes                                      
                       Balance                                            
______________________________________

Claims (8)

What is claimed:
1. An ophthalmic composition comprising polydimethysiloxane with a viscosity of 3-70 centistokes and a therapeutically effective amount of an ophthalmic drug of the formula ##STR3## wherein R1, R2 and R3 are any aliphatic combinations of C1 -C5, and R1 may also be hydrogen or the non-toxic pharmaceutically acceptable salts thereof.
2. A composition, as in claim 1 wherein said compound comprises a therapeutically effective amount of 2-t-butyl-3-methyl-5-(m-hydroxyphenyl)-1,3-oxazolidine.
3. A composition, as in claim 1 further comprising a therapeutically effective amount of one or more of anti-bacterials, antifungals, anti-oxidants, wetting agents, or preservatives.
4. A composition, as in claim 3 wherein said antibacterial comprises a therapeutically effective amount of chlorobutanol.
5. A composition, as in claim 1 wherein the balance of the composition is polydimethylsiloxane with a viscosity of 3 centistokes.
6. A composition, as in claim 1 wherein the balance of the composition is polydimethylsiloxane with a viscosity of 20 centistokes.
7. An ophthalmic composition, as in claim 1 wherein the compound of formula II comprises 0.00125-10% of the total composition.
8. A composition, as in claim 1 wherein the compound of formula II comprises 0.00125-2% of the total composition.
US07/045,913 1987-05-01 1987-05-01 Ophthalmic compositions and process for preparing Expired - Fee Related US4879304A (en)

Priority Applications (6)

Application Number Priority Date Filing Date Title
US07/045,913 US4879304A (en) 1987-05-01 1987-05-01 Ophthalmic compositions and process for preparing
EP88101032A EP0288659A1 (en) 1987-05-01 1988-01-25 Therapeutic opthalmic compositions containing silicone polymer fluids and a process for preparing same
JP10738588A JPS6452722A (en) 1987-05-01 1988-04-28 Ophthalmic composition
CA000565504A CA1309348C (en) 1987-05-01 1988-04-29 Ophthalmic composition containing polysiloxane
AU15315/88A AU609803B2 (en) 1987-05-01 1988-04-29 Ophthalmic compositions and process for preparing
KR1019880008502A KR890011602A (en) 1987-05-01 1988-07-08 Ophthalmic composition and preparation method thereof

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Cited By (2)

* Cited by examiner, † Cited by third party
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US6730691B1 (en) 2000-02-10 2004-05-04 Miles A. Galin Uses of alpha adrenergic blocking agents
US20100323978A1 (en) * 2009-06-22 2010-12-23 Calvin Hanna Non-aqueous oil delivery system for ophthalmic drugs

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AT393454B (en) * 1989-10-04 1991-10-25 Ido Dr Egerer EYE DROP ADDITION
US5518731A (en) * 1990-09-27 1996-05-21 Allergan, Inc. Nonaqueous fluorinated drug delivery vehicle suspensions
US6458376B1 (en) 1990-09-27 2002-10-01 Allergan, Inc. Nonaqueous fluorinated drug delivery suspensions
US5173298A (en) * 1990-09-27 1992-12-22 Allergan, Inc. Nonaqueous fluorinated drug delivery vehicle suspensions
IT1250701B (en) * 1991-07-24 1995-04-21 Angelini Francesco Ist Ricerca SOLID PHARMACEUTICAL COMPOSITION FOR ORAL USE BASED ON DAPIPRAZOLE
US5480914A (en) * 1994-05-06 1996-01-02 Allergan, Inc. Nonaqueous thixotropic drug delivery suspensions and methods of their use
DE19938668B4 (en) 1999-08-14 2006-01-26 Bausch & Lomb Inc. Artificial tears
CA2569726A1 (en) * 2004-06-08 2005-12-29 Ocularis Pharma, Inc. Hydrophobic ophthalmic compositions and methods of use
US20130345149A1 (en) * 2011-03-03 2013-12-26 Allergan, Inc. Silicone-based ophthalmic formulations
CA2829044A1 (en) * 2011-03-03 2012-09-07 Allergan, Inc. Silicone-based ophthalmic formulations
US20130029919A1 (en) 2011-07-26 2013-01-31 Allergan, Inc. Two part formulation system for opthalmic delivery

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US2727846A (en) * 1951-08-22 1955-12-20 Silicote Corp Siloxane-containing dressing
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US3993073A (en) * 1969-04-01 1976-11-23 Alza Corporation Novel drug delivery device
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US2727846A (en) * 1951-08-22 1955-12-20 Silicote Corp Siloxane-containing dressing
US3993073A (en) * 1969-04-01 1976-11-23 Alza Corporation Novel drug delivery device
US3880996A (en) * 1974-03-11 1975-04-29 Arthur I Fisher Topical analgesic preparation and method of using
US4012497A (en) * 1974-09-24 1977-03-15 Schering Aktiengesellschaft Drug excipient of silicone rubber
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Dow Corning 360 Medical Fluid. *
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Johansen and Bundgaard, J. Pharm. Sci, 72: 1294, (1983). *

Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US6730691B1 (en) 2000-02-10 2004-05-04 Miles A. Galin Uses of alpha adrenergic blocking agents
US20100323978A1 (en) * 2009-06-22 2010-12-23 Calvin Hanna Non-aqueous oil delivery system for ophthalmic drugs

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EP0288659A1 (en) 1988-11-02

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